Gemcitabine is a nucleoside anti-tumor drug. The mechanism of action of this drug is to antagonize nucleotide metabolism. After intracellular triphosphorylation in vivo, gemcitabine specifically interferes with nucleic acid metabolism and prevents cell division and reproduction by inhibiting the synthesis of deoxynucleoside triphosphate (dNTPs), interfering with cell replication by being incorporated into DNA or RNA molecules, competitively inhibiting DNA polymerase, and the like, thus eventually causing the death of tumor cells. Nucleoside anti-tumor drugs are prone to drug resistance, but ProTide prodrugs thereof can reduce the occurrence of drug resistance and have a good anti-tumor effect, among which a gemcitabine ProTide prodrug NUC-1031 has been clinically studied (Journal of Medical Chemistry 2014, 57, 1531-1542). However, ProTide prodrugs cannot reduce the toxic and side effects of drugs on non-tumor tissues.

With the rapid growth of tumors, some tumor tissues are farther and farther away from the nearest blood vessel, and oxygen supply is insufficient, resulting in tumor hypoxia (Nature review cancer 2002, 2: 38-47). Traditional anti-tumor drugs have good lethality to tumors near blood vessels, but have limited effects on tumors in hypoxic regions. Tumor hypoxic-activated prodrugs can specifically release anti-tumor active constituents in tumor hypoxic regions, thus killing tumors in the hypoxic regions (Chinese Journal of Cancer 2014, 33: 80-86). Hypoxic-activated prodrugs have a tumor targeting property, thus having a better safety performance, and a better anti-tumor effect when used in combination with traditional anti-tumor drugs, among which TH302 has been clinically studied and has a good therapeutic effect on pancreatic cancer (Journal of Clinical Oncology 2015, 33, 1475-1482).